ALS-linked FUS R521C disrupts arginine methylation of UBAP2L and stress granule dynamics

Mutations in the fused-in-sarcoma (FUS) gene have been linked to familial amyotrophic lateral sclerosis (fALS). FUS aggregates in the cytosol and associates with stress granules (SGs) in pathological cases, whereas FUS is normally found in the nucleus. However, little is known about how FUS mutations cause neurodegeneration in ALS, which is distinguished by FUS-positive inclusion and stress granules. In this study, we investigated the mechanism of abnormal cytoplasmic aggregate formation caused by ALS-linked FUS mutations. FUS R521C interacted more with ubiquitin-associated protein 2-like (UBAP2L) and protein arginine methyltransferase 1 (PRMT1) than FUS WT, and PRMT1 and UBAP2L are sequestered into FUS R521C-positive stress granules under oxidative stress. PRMT1 asymmetrically demethylates UBAP2L, which is required for both SG assembly and disassembly. Furthermore, in FUS R521C, arginine methylation of UBAP2L is reduced, and the loss of PRMT1 increases FUS-positive SGs in oxidative stress. These results imply that an aberrant interaction between FUS-R521C and PRMT1 causes insufficient arginine methylation of UBAP2L, resulting in abnormal FUS-R521C-positive SGs remaining in the cytoplasm. This study could lead to the identification of a new pathogenic mechanism and therapeutic targets for the FUS mutation, which has been associated with abnormally increased protein interactions in ALS. Graphical abstract